What is the recommended treatment and diagnostic approach for patients with suspected cryptococcal meningitis, including the use of CSF (Cerebrospinal Fluid) CRAG (Cryptococcal Antigen) testing and prophylaxis (preventive measures)?

Diagnostic and Treatment Approach for Cryptococcal Meningitis

CSF cryptococcal antigen (CRAG) testing is the gold standard for diagnosing cryptococcal meningitis, with sensitivity and specificity >90%, though false negatives can occur due to prozone effect, low antigen levels, or non-encapsulated strains. 1

Diagnostic Approach for Suspected Cryptococcal Meningitis

Initial Testing

• Perform lumbar puncture to obtain CSF for:
  • CSF cryptococcal antigen testing (primary diagnostic test)
  • India ink staining (less sensitive than CRAG)
  • Fungal culture
  • Routine studies (cell count, glucose, protein)
• Measure opening pressure during lumbar puncture (often elevated >20 cm H₂O)
• Obtain serum cryptococcal antigen (useful screening tool with high sensitivity)
• Collect blood cultures (positive in up to 75% of HIV-associated cryptococcal meningitis)

Important Considerations for CSF CRAG Testing

• CSF CRAG testing has replaced India ink stain as the rapid diagnostic method 1
• False negative results may occur due to:
  • Prozone effect (high titers of antigen)
  • Low levels of antigen
  • Non-encapsulated Cryptococcus strains 1, 2
• If clinical suspicion is high despite negative CSF CRAG:
  • Repeat testing with diluted samples to overcome prozone effect
  • Perform fungal cultures (may take days to weeks)
  • Consider brain MRI to evaluate for cryptococcomas

CSF Collection and Handling

• Collect as much CSF as possible (minimum 1 mL, more is better)
• Do not refrigerate CSF specimens
• Process samples promptly 1

Treatment of Cryptococcal Meningitis

Induction Therapy (First 2 Weeks)

• Amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for at least 2 weeks 3
• For patients with renal dysfunction: Use lipid formulations of amphotericin B
  • Liposomal amphotericin B (3-4 mg/kg/day IV) or
  • Amphotericin B lipid complex (5 mg/kg/day IV) 3

Consolidation Therapy (Next 8 Weeks)

• Fluconazole 400 mg daily for 8 weeks 3, 4

Maintenance Therapy

• Fluconazole 200 mg daily until immune reconstitution occurs 3, 4
• For HIV patients: Continue until CD4 >100 cells/μL and HIV viral load is undetectable for at least 12 months 3

Management of Increased Intracranial Pressure

• If opening pressure >25 cm H₂O and symptoms of increased ICP present:
  • Perform daily therapeutic lumbar punctures
  • Remove CSF to reduce opening pressure by 50% or to normal pressure
  • Continue until pressure normalizes
• Consider CSF shunting for patients who cannot tolerate daily lumbar punctures 3

Special Considerations for HIV-Infected Patients

• Delay initiation of antiretroviral therapy (ART) until after completion of induction therapy (at least 2 weeks) to prevent immune reconstitution inflammatory syndrome (IRIS) 3
• Screen HIV patients with CD4 <100 cells/μL for serum cryptococcal antigen in high prevalence regions 5
• For HIV patients with cryptococcal meningitis, maintenance therapy with fluconazole should continue until CD4 >100 cells/μL and viral load is undetectable 1, 3

Monitoring Treatment Response

• Follow CSF cultures until negative (typically 10-12 weeks of therapy)
• Monitor CSF cryptococcal antigen titers (a rise during therapy suggests treatment failure or relapse)
• A CSF titer >1:8 after completion of therapy may indicate treatment failure 1

Prevention of Adverse Effects

• Monitor renal function and electrolytes during amphotericin B therapy
• Administer pre-infusion saline (500 mL) to reduce nephrotoxicity
• Monitor complete blood counts during flucytosine therapy (bone marrow suppression)
• Adjust flucytosine dose in patients with renal impairment 3

By following this comprehensive diagnostic and treatment approach, clinicians can effectively manage cryptococcal meningitis and improve patient outcomes.